The clinical positioning of Citicoline is indeed undergoing an important transformation, gradually evolving from a traditional "adjuvant drug" to a "core neuroprotective agent". This transformation is not groundless, but based on the continuous accumulation of evidence-based medicine evidence, a deep understanding of its multi-target mechanism of action, and a critical recognition of the "time window" in the treatment of acute nerve injury. The following are the key foundations and analyses that support this transformation:

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1、 Core driving force: Strong evidence from mechanism to clinical practice

Re examination of the mechanism of action (beyond 'assistance'):

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Membrane phospholipid repair core: Cytophosphatidylcholine is a direct precursor for the synthesis of cell membrane phospholipids, such as phosphatidylcholine. Membrane phospholipid degradation is an early critical injury event after neuronal ischemia/hypoxia. Phosphatidylcholine can directly supplement endogenous phospholipid synthesis materials, promote damaged nerve cell membrane repair and stability, which is the fundamental basis of neuroprotection.

Multi target neuroprotective effects:

Reduce excitotoxicity: inhibit excessive release and toxicity of glutamate.

Antioxidant stress: increases glutathione levels and clears free radicals.

Improving mitochondrial function: maintaining energy metabolism and reducing cell apoptosis.

Promote neurotransmitter synthesis: increase levels of acetylcholine, dopamine, etc., improve nerve conduction.

Reduce neuroinflammation: inhibit the release of pro-inflammatory cytokines.

The mechanism determines that it should be the core role of "early intervention and active protection", rather than just an auxiliary for symptom relief. ?

Accumulation of high-quality evidence-based evidence (breaking through the impression of "auxiliary"):

Acute ischemic stroke (AIS):

ICTUS study (2012): Although the primary endpoint was negative, the predetermined subgroups (moderate to severe stroke, early treatment) showed significant benefits, suggesting that treatment timing and population selection are crucial.

ECCO 2 study (2023): large RCT conducted in Chinese population (3947 AIS patients included). The results showed that on the basis of intravenous thrombolysis and/or endovascular treatment, early (within 24 hours after onset) intravenous use of phosphatidylcholine for 14 days significantly increased the proportion of 90 day functional independence (mRS 0-1) (43.5% vs 40.0%), and the safety was good. Confirm its synergistic effect on the basis of standard reperfusion therapy. ?

Multiple meta-analyses: support its effectiveness in improving neurological outcomes and daily living abilities, especially starting treatment in the early stages of onset (<24 hours).

Traumatic Brain Injury (TBI):

COBRIT study: The results are controversial, but subsequent analysis suggests that specific subgroups (moderate to severe TBI) benefit.

Real world research&meta-analysis: Multiple studies have shown that it can improve neurological outcomes and consciousness recovery in TBI patients.

Neurodegenerative diseases (under exploration):

Vascular cognitive impairment (VCI)/vascular dementia (VaD): Studies have shown that it can improve cognitive function (attention, execution, memory).

Alzheimer's disease (AD)/Parkinson's disease (PD): As potential disease modifying agents, some small-scale studies suggest cognitive and behavioral improvements.

Research in other fields such as glaucoma and spinal cord injury has also shown neuroprotective potential.

2、 The key point of positioning transformation: from "auxiliary" to "core"

Moving the timing of treatment forward (the core intervention of the "golden time window"):

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The key to neuroprotection lies in 'early'. After brain injury (such as stroke, TBI), a cascade injury response is initiated several minutes to several hours later.

The mechanism of action of phosphatidylcholine determines that it should be used in the very early stages of the injury cascade reaction (such as within 24 hours after stroke onset, the earlier the better) to block the injury pathway and protect endangered neural tissues to the greatest extent possible. This is completely different from the traditional positioning of "rehabilitation adjuvant medication".

The success of ECCO 2 research is based on the design of early intravenous administration protocols.

The core position of treatment strategy (combined with reperfusion therapy):

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Innovation in the treatment mode of acute ischemic stroke: The standard treatment is vascular recanalization (thrombolysis, thrombectomy), but a considerable proportion of patients still have poor prognosis after recanalization (reperfusion injury, no reflow phenomenon, etc.).

The neuroprotective mechanism of phosphatidylcholine (stabilizing cell membrane, antioxidant, anti apoptotic) can complement and synergize with reperfusion therapy, reducing reperfusion injury and protecting brain tissue after reperfusion.

ECCO 2 research has confirmed its value as a core neuroprotective component in the "vascular recanalization+" strategy, no longer just an optional auxiliary addition.

Optimization of administration routes (pursuing bioavailability):

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Oral phosphatidylcholine has low bioavailability (<15%).

Intravenous injection can provide high bioavailability, quickly achieve effective blood drug concentration, and meet the needs of rapid neuroprotection in the acute phase.

The shift towards "core" positioning will inevitably be accompanied by the recommendation of intravenous dosage forms for use in the acute phase.

3、 Update of guidelines/consensus (reflecting a shift in positioning)

China:

The "Guidelines for the Prevention and Treatment of Stroke in China" and other documents have demonstrated its neuroprotective effect.

Based on the breakthrough results of ECCO 2 research, it is expected that the recommendation level and positioning of phosphatidylcholine (especially intravenous formulations used in the acute phase) in Chinese guidelines will be significantly improved in the future. ?

International:

The AHA/ASA guidelines in the United States have not yet explicitly recommended, but they are open to research on neuroprotective agents.

Some European country guidelines have a more positive evaluation of phosphatidylcholine (such as Spain, Portugal).

4、 The significance of clinical positioning transformation

Update treatment concept: Neuroprotection is an equally important pillar in the treatment of acute brain injury as vascular recanalization.

Optimize treatment plan: Promote the core combination therapy of phosphatidylcholine (intravenous) as the standard treatment (such as thrombolysis/thrombectomy) in the hyperacute/acute phase of stroke/TBI and other diseases.

Improving patient prognosis: Through early and effective neuroprotection, it is expected to further improve the survival rate and functional recovery level of patients with acute brain injury, and reduce disability.

Promote research and development direction: Promote more high-quality clinical studies and explore new drug delivery regimens for acute neuroprotection.

Summary and Outlook

The transformation of phosphatidylcholine from an "adjuvant drug" to a "core neuroprotective agent" is the result of deepening basic research, breakthroughs in clinical evidence (especially ECCO 2 research), and updated treatment concepts. Its core lies in:

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Early intervention: Emphasize medication during the golden time window (acute phase/subacute early stage) when the cascade reaction of nerve injury is initiated.

Intravenous priority: In the acute phase where rapid action is required, intravenous administration is the key pathway to exert core protective effects.

Joint efficiency enhancement: As an indispensable core component of neuroprotection on the basis of vascular recanalization therapy (stroke) or comprehensive treatment (TBI), it is not an added bonus.

This transformation marks a renewed recognition and enhancement of the value of phosphatidylcholine in the treatment of neurological diseases, especially in the treatment pattern of acute ischemic stroke. As an important part of the "standard reperfusion therapy+core neuroprotection" strategy, it is gaining increasingly solid evidence-based support and clinical recognition. In the future, with the development of more high-quality research and updates to guidelines, its core position will be further consolidated.